Mice and rats are a fundamental component of drug discovery research. Standard outbred stocks and inbred strains of rodents are used extensively for drug safety and pharmacokinetic testing. Our ability to generate specific mutants through transgene insertion or gene knockouts has greatly expanded their utility.
The NIH has begun the Knock-Out Mouse Project (KOMP), an ambitious program to knock out every gene in the mouse genome. These knockouts are extraordinarily useful for modeling human diseases and elucidating key metabolic and regulatory pathways.
These valuable animals have been widely disseminated throughout the research community. Unfortunately, there is a widespread perception that the phenotypes displayed by these animals are attributable to the genetic manipulations they carry. This is not necessarily true. No gene acts alone, but in concert with all the other expressed genes in the organism. Even classic single-gene Mendelian traits, such as sickle cell anemia, display phenotypic variation due to the modifying effects of other genes. Thus the genetic background must be considered in these studies. Rapid, cost-effective, and comprehensive genotyping is essential.
Mice and rats fall into two broad classes of genetic background. Inbred strains of animals have been generated by repeated sibling mating so that all the animals in an inbred strain are considered genetically identical. Outbred stocks of animals are managed to maximize genetic diversity between individuals. However, all outbred stocks start with a limited population and therefore are not nearly as heterogeneous as populations in the wild. Animals from an outbred stock will share common characteristics.
The genetic background of animals used in research is of critical importance, as it can have profound effects on the observed phenotype. A phenotype can be profound in one strain and not affect another. In addition, there are cases in which the phenotype of interest was found to be an artifact of a contributing background strain.